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and Keller, L. (2005). Clonal reproduction (2001). Genetic variation in a host- sexes reveals ontogenetic conflict in by males and females in the little fire ant. parasite association: potential for Drosophila. Evolution Int. J. Org. Nature 435, 1230-1234. coevolution and frequency-dependent Evolution 98, 1671–1675. 5. Hamilton, W.D., Axelrod, R., and Tanese, selection. Evolution Int. J. Org. Evolution R. (1990). Sexual reproduction as an 55, 1136–1145. adaptation to resist parasites (A Review). 8. Liersch, S., and Schmid-Hempel, P. Institute of Evolutionary Biology, Proc. Natl. Acad. Sci. USA 87, (1998). Genetic variation within social University of Edinburgh, West Mains 3566–3573. insect colonies reduces parasite load. Road, Edinburgh EH9 3JT, UK. 6. Kondrashov, A.S. (1982). Selection Proc. R. Soc. Lond. B. Biol. Sci. 265, against harmful mutations in large sexual 221–225. E-mail: [email protected] and asexual populations. Genet. Res. 40, 9. Chippendale, A.K., Gibson, J.R., and 325–332. Rice, W.R. (2001). Negative genetic 7. Carius, H.J., Little, T.J., and Ebert, D. correlation for adult fitness between DOI: 10.1016/j.cub.2005.07.001

Neurotransmission: Emerging requires a sustained (5–10 minute) activation of presynaptic CB1 Roles of Endocannabinoids receptors [12,13]. Modulation of synaptic transmission by endocannabinoids Postsynaptic release of endocannabinoids can inhibit presynaptic was initially studied using non- neurotransmitter release on short and long timescales. This retrograde physiological methods, such as inhibition occurs at both excitatory and inhibitory synapses and may seconds-long depolarization or provide a mechanism for synaptic gain control, short-term associative application of high-affinity plasticity, reduction of synaptic crosstalk, and metaplasticity. metabotropic receptor agonists, to evoke endocannabinoid release. Anatol C. Kreitzer [3], which can then diffuse to But the modulatory role of adjacent presynaptic terminals and endocannabinoids during normal Endocannabinoids are a class of suppress neurotransmitter release synaptic activity was not known. lipophilic signaling molecules that for tens of seconds [4,5]. A similar Brenowitz and Regehr [14] found are synthesized and released by phenomenon has been observed that depolarization-evoked postsynaptic neurons in response at excitatory synapses and is endocannabinoid release from to increases in intracellular known as depolarization-induced cerebellar Purkinje cells requires calcium levels or activation of suppression of excitation (DSE) [6]. high levels of intracellular calcium, metabotropic receptors. As their In addition to depolarization- suggesting that depolarization name implies, endocannabinoids mediated calcium entry, activation alone may not play a prominent activate the same G protein- of metabotropic glutamate and role in the release of coupled receptors as the active acetylcholine receptors can drive endocannabinoids under normal compounds in Cannabis sativa endocannabinoid release through physiological conditions. (marijuana). The primary neuronal a separate biosynthetic pathway Another study, in the subtype of this receptor, known as [7,8]. Receptor-mediated cerebellum, by Maejima et al. [7] CB1, is widely distributed in the endocannabinoid production found that 50–100 Hz activation mammalian brain and is expressed requires phospholipase Cβ (PLCβ) of excitatory parallel fiber in presynaptic terminals, where it [9], an enzyme which is activated synapses onto a Purkinje cell can inhibit neurotransmitter by G protein signaling and could yield a transient 10–15% release. The endocannabinoid modulated by calcium. Thus, heterosynaptic inhibition of system is thus well suited for rapid increases in intracellular calcium neurotransmitter release at retrograde signaling across can directly stimulate excitatory climbing fiber activated synapses. Recent endocannabinoid production via synapses on the same Purkinje studies are beginning to elucidate PLD, while at the same time cell. This synaptically evoked the physiological roles of this increasing the efficacy of inhibition was mediated by signalling. receptor-driven PLCβ-mediated endocannabinoids and required Retrograde signaling by biosynthesis. This receptor-driven activation of postsynaptic endocannabinoids was first release is critical for metabotropic glutamate observed in the cerebellum and endocannabinoid-mediated long- receptors, an early indication that hippocampus as a phenomenon term depression (LTD) of receptor-driven endocannabinoid termed depolarization-induced neurotransmitter release at both release is critical under more suppression of inhibition (DSI) [1,2]. excitatory and inhibitory synapses physiological conditions. DSI is a short-term depression of [10–12]. Although LTD can be The first systematic study of neurotransmitter release that can elicited by short (1 second) synaptically evoked be elicited by postsynaptic presynaptic bursts sufficient to endocannabinoid release was that depolarization sufficient to activate activate postsynaptic of Brown et al. [15], again in the voltage-sensitive calcium metabotropic glutamate cerebellum. Following brief trains channels. Increases in intracellular receptors, the subsequent of parallel fiber stimulation, they calcium levels stimulate the receptor-driven endocannabinoid observed a transient ~50% production of endocannabinoids, release may feature slower inhibition of neurotransmitter perhaps via phospholipase D (PLD) kinetics since LTD induction release from parallel fibers, which Current Biology Vol 15 No 14 R550

was mediated by nor climbing fiber stimulation promoting synaptic endocannabinoid release from prior to a parallel fiber burst independence. Purkinje cells. Varying the yields significant While the suppression of frequency of parallel fiber endocannabinoid release. excitatory synapses by stimulation or the number of However, when climbing fiber endocannabinoids provides a stimuli in a train altered the stimulation occurs during or mechanism for limiting synaptic magnitude of this inhibition, which immediately after a parallel fiber excitation, suppression of arose largely from metabotropic burst, a short-term depression of inhibitory synapses may play a glutamate receptor-driven neurotransmitter release is very different role — regulating endocannabinoid release. observed. Thus, Purkinje cell the induction of LTP at nearby Importantly, this retrograde synapses can act as coincidence excitatory synapses. In the signaling was found to be detectors, releasing hippocampus, endocannabinoid- synapse specific — only the endocannabinoids at only those mediated suppression of GABA activated synapses were parallel fiber synapses that are release onto CA1 pyramidal inhibited, whereas other nearby simultaneously active with neurons occurs on both short and synapses were unaffected. climbing fiber firing, giving rise to long timescales. Depolarization of The larger magnitude of a novel form of short-term CA1 pyramidal neurons elicits homosynaptic parallel fiber associative plasticity. DSI, a transient suppression of inhibition relative to A new study by Marcaggi and inhibitory synapses lasting tens of heterosynaptic climbing fiber Attwell [18] provides a different seconds. Carlson et al. [19] found inhibition following high frequency perspective on the physiological that a short excitatory presynaptic parallel fiber stimulation can be role of endocannabinoid signaling. burst, normally ineffective at explained by the different In the studies of synaptically inducing LTP, could elicit LTP if sensitivities of parallel fiber and activated endocannabinoid delivered during DSI. climbing fiber neurotransmitter signaling described above, Similarly, an endocannabinoid- release to presynaptic parallel fiber synapses were mediated LTD of inhibitory modulation, as well as by the stimulated by an electrode placed neurotransmitter release (iLTD) spatial segregation of these in the molecular layer of cerebellar onto CA1 pyramidal neurons [20] synapses on the Purkinje cell cortex. This method yields a also facilitates the induction of dendritic tree. Thus, ‘dense’ pattern of synaptic LTP at nearby excitatory endocannabinoids may play an activation in which nearly all the synapses. Because iLTD is important role in short-term parallel fiber synapses in a synapse-specific and long-lasting, synaptic gain control. If some particular Purkinje cell dendritic the subsequent priming of LTP is excitatory synapses onto a region are active and glutamate also long-lasting and can be postsynaptic cell become very spillover can effectively activate restricted to synapses on a small active, local endocannabinoid perisynaptic metabotropic region of dendrite. release can reduce their strength, glutamate receptors, thereby Endocannabinoids thus play ensuring that a small set of active enhancing endocannabinoid diverse physiological roles in synapses will not control release. But it is not known different cell types and brain postsynaptic firing. whether such dense synapse regions. Their specific role may Although high frequency parallel activation occurs in vivo. vary depending upon temporal fiber trains give rise to retrograde To test whether sparse synaptic and spatial patterns of neuronal inhibition by endocannabinoids, in activation can also elicit activity, regulation of glutamate vivo firing of cerebellar granule endocannabinoid release, uptake, and the kinetics of cells occurs in short bursts [16]. A Marcaggi and Attwell [18] placed endocannabinoid biosynthesis, recent study by Brenowitz and their stimulus electrode in the transport, and degradation. It is Regehr [17] found that, although cerebellar granule cell layer, which clear, however, that such bursts alone do not yield yields a more dispersed pattern of endocannabinoids serve a unique endocannabinoid release, when synapse activation onto Purkinje and important function in the paired with climbing fiber cells. With sparse activation of rapid retrograde regulation of stimulation, endocannabinoid- parallel fiber synapses, synaptic strength in the central mediated retrograde inhibition of metabotropic glutamate receptor nervous system. parallel fiber neurotransmitter activation and endocannabinoid release becomes quite prominent. release did not occur in response References Although metabotropic glutamate to either short high-frequency 1. Llano, I., Leresche, N., and Marty, A. (1991). Calcium entry increases the receptors are not strictly required parallel fiber bursts or pairing of sensitivity of cerebellar Purkinje cells to for this inhibition, activation of parallel fiber and climbing fiber applied GABA and decreases inhibitory synaptic currents. Neuron 6, 565–574. metabotropic glutamate receptors stimulation. Thus, 2. Pitler, T.A., and Alger, B.E. (1994). greatly enhances the sensitivity of endocannabinoid release may Depolarization-induced suppression of endocannabinoid release to specifically limit neurotransmitter GABAergic inhibition in rat hippocampal pyramidal cells: G-protein involvement in postsynaptic calcium. release at excitatory synapses a presynaptic mechanism. Neuron 13, The timing of climbing fiber onto dendrites receiving dense 1447–1455. 3. Di Marzo, V., Fontana, A., Cadas, H., stimulation is critical — neither activation, thereby reducing Schinelli, S., Cimino, G., Schwartz, J.C., climbing fiber stimulation alone, further glutamate spillover and and Piomelli, D. (1994). Formation and Dispatch R551

inactivation of endogenous cannabinoid serves as a coincidence detector bursts evoke synapse-specific anandamide in central neurons. Nature through its Ca2+ dependency for retrograde inhibition mediated by 372, 686–691. triggering retrograde endocannabinoid endogenous cannabinoids. Nat. 4. Wilson, R.I., and Nicoll, R.A. (2001). signal. Neuron 45, 257–268. Neurosci. 6, 1048–1057. Endogenous cannabinoids mediate 10. Robbe, D., Kopf, M., Remaury, A., 16. Chadderton, P., Margrie, T.W., and retrograde signalling at hippocampal Bockaert, J., and Manzoni, O.J. (2002). Hausser, M. (2004). Integration of quanta synapses. Nature 410, 588–592. Endogenous cannabinoids mediate long- in cerebellar granule cells during sensory 5. Ohno-Shosaku, T., Maejima, T., and term synaptic depression in the nucleus processing. Nature 428, 856–860. Kano, M. (2001). Endogenous accumbens. Proc. Natl. Acad. Sci. USA 17. Brenowitz, S.D., and Regehr, W.G. cannabinoids mediate retrograde signals 99, 8384–8388. (2005). Associative short-term synaptic from depolarized postsynaptic neurons 11. Sung, K.W., Choi, S., and Lovinger, D.M. plasticity mediated by to presynaptic terminals. Neuron 29, (2001). Activation of group I mGluRs is endocannabinoids. Neuron 45, 419–431. 729–738. necessary for induction of long-term 18. Marcaggi, P., and Attwell, D. (2005). 6. Kreitzer, A.C., and Regehr, W.G. (2001). depression at striatal synapses. J. Endocannabinoid signaling depends on Retrograde inhibition of presynaptic Neurophysiol. 86, 2405–2412. the spatial pattern of synapse activation. calcium influx by endogenous 12. Chevaleyre, V., and Castillo, P.E. (2003). Nat. Neurosci. 8, 776–781. cannabinoids at excitatory synapses Heterosynaptic LTD of hippocampal 19. Carlson, G., Wang, Y., and Alger, B.E. onto Purkinje cells. Neuron 29, 717–727. GABAergic synapses: a novel role of (2002). Endocannabinoids facilitate the 7. Maejima, T., Hashimoto, K., Yoshida, T., endocannabinoids in regulating induction of LTP in the hippocampus. Aiba, A., and Kano, M. (2001). excitability. Neuron 38, 461–472. Nat. Neurosci. 5, 723–724. Presynaptic inhibition caused by 13. Ronesi, J., Gerdeman, G.L., and 20. Chevaleyre, V., and Castillo, P.E. (2004). retrograde signal from metabotropic Lovinger, D.M. (2004). Disruption of Endocannabinoid-mediated glutamate to cannabinoid receptors. endocannabinoid release and striatal metaplasticity in the hippocampus. Neuron 31, 463–475. long-term depression by postsynaptic Neuron 43, 871–881. 8. Kim, J., Isokawa, M., Ledent, C., and blockade of endocannabinoid membrane Alger, B.E. (2002). Activation of transport. J. Neurosci. 24, 1673–1679. muscarinic acetylcholine receptors 14. Brenowitz, S.D., and Regehr, W.G. Department of Psychiatry and enhances the release of endogenous (2003). Calcium dependence of cannabinoids in the hippocampus. J. retrograde inhibition by Behavioral Sciences, Stanford Neurosci. 22, 10182–10191. endocannabinoids at synapses onto University, 1201 Welch Road, Palo Alto, 9. Hashimotodani, Y., Ohno-Shosaku, T., Purkinje cells. J. Neurosci. 23, California 94305, USA. Tsubokawa, H., Ogata, H., Emoto, K., 6373–6384. Maejima, T., Araishi, K., Shin, H.S., and 15. Brown, S.P., Brenowitz, S.D., and Kano, M. (2005). Phospholipase Cβ Regehr, W.G. (2003). Brief presynaptic DOI: 10.1016/j.cub.2005.07.005

Cytoskeleton: Microtubules Born both processes simultaneously — a microtubule can be nucleated at on the Run a site on the side of an existing microtubule and transported as it grows. This type of mechanism The organization of microtubules into large arrays determines cell may apply to a wide range of cells morphology and structure. Recent work in the fission yeast describes a having non-centrosomal novel mechanism for microtubule self-organization in the absence of microtubule arrays, including centrosomes; this mechanism may function in a variety of cell types epithelial cells, neurons, muscle found in diverse organisms. cells and plant cells. Progress in understanding how Bret E. Becker and How are microtubules organized non-centrosomal microtubule Lynne Cassimeris into larger arrays? Are they ‘born’ arrays are organized has come or are they ‘made’? In animal cells, from experiments using the fission The microtubule cytoskeleton most microtubule arrays are ‘born’ yeast, Schizosaccharomyces organizes the internal structures — they are nucleated by the pombe [5–7]. This rod-shaped within the cell and provides centrosome (the major yeast builds several relatively directional information for the microtubule-organizing center simple microtubule arrays during motor proteins that run along the (MTOC) of animal cells), which its life cycle, including four microtubules. Organization and typically sits alongside the nucleus distinct bundles of non- directional information come from near the center of the cell [2]. With centrosomal microtubules during the polarity built into microtubules the microtubule minus ends all interphase [8] (Figure 1A,B). Each as they assemble from tubulin located in the center of the cell, interphase bundle minimally heterodimers. The initial step in the microtubule plus ends grow contains a pair of anti-parallel microtubule assembly — out in a radial pattern, extending in microtubules with overlapping nucleation — also defines the all directions toward the plasma minus ends located near the polarity of the microtubule. In membrane. However, other nucleus and plus ends extending cells, microtubules are nucleated microtubule arrays are ‘made’ — out toward the periphery. The by complexes known as γTuCs, individual microtubules free in the polarity and organization of the which contain γ-tubulin and a cytoplasm are gathered and interphase microtubules cohort of additional proteins. The sorted into a polarized array by the determines the sites of new cell γTuCs bind and stabilize the actions of motor proteins [3]. The growth and cell shape. These ‘minus’ end of the microtubule, meiotic spindle in some organisms interphase microtubules are while the dynamic ‘plus’ end can form by this process [4]. nucleated at sites termed extends away from the nucleation Recent work from Janson et al. [5] interphase MTOCs (iMTOCs, site and grows and shortens by now demonstrates that Figure 1) and the molecular dynamic instability [1]. microtubule arrays can arise from characterization of these iMTOCs